Biology subjects

Harrison, B.

Publications and source records attributed to Harrison, B..

15 recordsLinked to original sources

bioRxiv2026

Adaptive spatiotemporal filtering of social electrosensory signals by cerebellar feedback

Sensory feedback can suppress predictable input, yet most research on this mechanism used simplified stimuli that do not capture the spatial and temporal structure of natural signals. We examined how cerebellum-like feedback, in brown ghost knifefish, shapes the encoding of realistic social electrosensory signals. These naturalistic signals replicated the spatial structure of social signals, spanned the range of typical AM beat frequencies, and incorporated movement-related contrast envelopes. Single-unit recordings were obtained from electrosensory lateral line lobe pyramidal cells while a conspecific-like signal was delivered. Responses were compared before and after pharmacological blockade of descending cerebellar feedback. As expected, feedback strongly attenuated responses to spatially-realistic low-frequency beats but did not alter beat-cycle coding at higher frequencies. However, feedback reduced the neural representation of movement-related contrast envelopes across all beat frequencies. Using information-theoretic tools, we showed that feedback strength adapts dynamically to the stimulus contrast over the past few hundred ms. Furthermore, we examined how the spatial coding by the pyramidal cell population is influenced by feedback. We show that feedback enhances localization cues. This improvement arose because feedback reduces weak background responses while not affecting the strongest responses, thereby increasing spatial contrast. These findings show that the same descending pathway jointly filters temporal and spatial features of the full range of natural signals, adapting to recent input statistics. This process exemplifies a general mechanism by which a predictive feedback can improve the efficiency of natural sensory representations.

neuroscience↗

bioRxiv2026

Oligella otitidis sp. nov., isolated from middle ear discharge of children with chronic suppurative otitis media

Oligella otitidis MSHR-50489EDL strain (ATCC: TSD-462-; DSMZ: DSM 118617) is a new species of the genus Oligella that was isolated from a middle ear discharge swab from a child with chronic suppurative otitis media (CSOM). This Gram-negative coccobacillus produces small, circular, smooth, whitish-opaque and occasionally mucoid colonies. It grows in aerobic conditions at a temperature range from 25-42{degrees}C. Phylogenetic analysis demonstrates a relationship to other species of the genera Oligella and average nucleotide identity and digital DNA-DNA hybridization values indicate a distinct species in comparison to other Oligella species. Thus far, the majority of isolates exhibit resistance to ciprofloxacin, the first line treatment for CSOM.

microbiology↗

bioRxiv2025

Mitochondrial Dysfunction Drives Age-Related Degeneration of the Thoracic Aorta

This study investigated the role of mitochondrial function in aortic aging. As the aorta ages, it becomes stiffer and less compliant, increasing the risk of aneurysmal disease, hypertension, and diastolic dysfunction. Given the role of mitochondrial dysfunction in non-age related aortopathies and as a hallmark of aging, we investigated its contribution to the aging aorta. Both male and female young (5-6 month) and aged (24-25 month) C57Bl/6J mice received mitochondrial-targeted peptide elamipretide (ELAM; SS-31) for 8 weeks. ELAM restored complex II-linked respiration in aged mice to values seen in young mice, while also improving relative phosphorylative flux. ELAM treatment also reduced inflammatory MMP9 expression and elastin breaks in aged mice. Bulk RNAseq analysis revealed that ELAM treatment significantly affected the aortic transcriptome in an age-dependent manner, reducing the expression of senescent and associated pro-inflammatory genes. Mitochondrial dysfunction thus drives aortic aging and is a potential therapeutic target for future study. TeaserLoss of mitochondrial function with age drives degeneration of the aging aorta, and thus is a potential target for therapy.

cell biology↗

bioRxiv2025

Dynamic hyperplastic cardiac growth in Burmese pythons

Cardiomyocytes hyperplasia is the primary form of fetal heart growth, whereas this proliferative capacity is largely lost in adults across most species. The limited ability of adult cardiomyocytes to re-enter the cell cycle is a major cause of cardiac injury-induced morbidity and mortality. Here, we report that post-prandial Burmese python cardiomyocytes activate cell cycle re-entry to promote persistent cardiac growth. Burmese pythons normally eat large meals infrequently, resulting in reversible cardiac hypertrophy. We found that frequent feeding of large meals amplifies the modest post-prandial cardiac proliferation identified in an infrequent feeding interval. By activating E2F and Forkhead Box M1 (FoxM1) pro-proliferation transcriptional networks, frequently fed Burmese pythons initiate cardiomyocyte hyperplasia. These findings identify hyperplasia as a natural means of sustained cardiac growth in Burmese pythons and support the use of pythons as a new model for investigating proliferative cardiac remodeling.

cell biology↗

bioRxiv2025

Functional Specialization of S-Adenosylmethionine Synthases Links Phosphatidylcholine to Mitochondrial Function and Stress Survival

S-adenosylmethionine (SAM), produced by SAM synthases, is critical for various cellular regulatory pathways and the synthesis of diverse metabolites. Studies have often equated the effects of knocking down one synthase with broader SAM-dependent outcomes such as histone methylation or phosphatidylcholine (PC) production. Humans and many other organisms express multiple SAM synthases. Evidence in Caenorhabditis elegans, which possesses four SAM synthase genes, suggest that the enzymatic source of SAM impacts its function. For instance, loss of sams-1 leads to enhanced heat shock survival and increased lifespan, whereas reducing sams-4 adversely affects heat stress survival. Here, we show that SAMS-1 contributes to a variety of intermediary metabolic pathways, whereas SAMS-4 is more important to generate SAM for methylation reactions. We demonstrate that loss of sams-1 exerts age-dependent effects on nuclear-encoded mitochondrial gene expression, mitochondrial metabolites, and may induce mitophagy. We propose a mechanistic model where reduced SAM from SAMS-1 acts through PC to impact mitochondria, thereby enhancing survival during heat stress.

cell biology↗

bioRxiv2024

Clinicogenomic characterization of inflammatory breast cancer

BackgroundInflammatory breast cancer (IBC) is a rare and poorly characterized type of breast cancer with an aggressive clinical presentation. The biological mechanisms driving the IBC phenotype are relatively undefined--partially due to a lack of comprehensive, large-scale genomic studies and limited clinical cohorts. Patients and MethodsA retrospective analysis of 2457 patients with metastatic breast cancer who underwent targeted tumor-only DNA-sequencing was performed at Dana-Farber Cancer Institute. Clinicopathologic, single nucleotide variant (SNV), copy number variant (CNV) and tumor mutational burden (TMB) comparisons were made between clinically confirmed IBC cases within a dedicated IBC center versus non-IBC cases. ResultsClinicopathologic differences between IBC and non-IBC cases were consistent with prior reports--including IBC being associated with younger age at diagnosis, higher grade, and enrichment with hormone receptor (HR)-negative and HER2-positive tumors. The most frequent somatic alterations in IBC involved TP53 (72%), ERBB2 (32%), PIK3CA (24%), CCND1 (12%), MYC (9%), FGFR1 (8%) and GATA3 (8%). A multivariate logistic regression analysis revealed a significant enrichment in TP53 SNVs in IBC; particularly in HER2-positive and HR-positive disease which was associated with worse outcomes. Tumor mutational burden (TMB) did not differ substantially between IBC and non-IBC cases and a pathway analysis revealed an enrichment in NOTCH pathway alterations in HER2-positive disease. ConclusionTaken together, this study provides a comprehensive, clinically informed landscape of somatic alterations in a large cohort of patients with IBC. Our data support higher frequency of TP53 mutations and a potential enrichment in NOTCH pathway activation--but overall; a lack of major genomic differences. These results both reinforce the importance of TP53 alterations in IBC pathogenesis as well as their influence on clinical outcomes; but also suggest additional analyses beyond somatic DNA-level changes are warranted.

genomics↗

bioRxiv2023

Cell age drives asynchronous transcriptome aging

Organs age at different rates within a single individual. Such asynchrony in aging has been widely observed at multiple levels, from functional hallmarks, such as anatomical structures and physiological processes, to molecular endophenotypes, such as the transcriptome and metabolome. However, we lack a conceptual framework to understand why some components age faster than others. Just as demographic models explain why aging evolves, here we test the hypothesis that demographic differences among cell types, determined by cell-specific differences in turnover rate, can explain why the transcriptome shows signs of aging in some cell types but not others. Through analysis of mouse single-cell transcriptome data across diverse organs and ages, we find that cellular age explains a large proportion of the variation in the age-related increase in transcriptome variance. We further show that long-lived cells are characterized by relatively high expression of genes associated with proteostasis, and that the transcriptome of long-lived cells shows greater evolutionary constraint than short-lived cells. In contrast, in short-lived cell types the transcriptome is enriched for genes associated with DNA repair. Based on these observations, we develop a novel heuristic model that explains how and why aging rates differ among cell types.

systems biology↗

bioRxiv2022

Long wavelength light reduces the negative consequences of dim light at night in the Cntnap2 mouse model of autism.

Many patients with autism spectrum disorders (ASD) show disturbances in their sleep/wake cycles, and may be particularly vulnerable to the impact of circadian disruptors. We have previously shown that exposure to dim light at night (DLaN) in contactin associated protein-like 2 knock out (Cntnap2 KO) mice disrupts diurnal rhythms, increases repetitive behaviors while reducing social interactions. These negative effects of DLaN may be mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) expressing the photopigment melanopsin, which is maximally sensitive to blue light (480nm). In this study, we used a light-emitting diode (LED) array that enabled us to shift the spectral properties of the DLaN while keeping the intensity at 10 lx. First, using wild-type (WT) mice, we confirmed that the short-wavelength enriched lighting produced strong acute suppression of locomotor activity (masking), robust light-induced phase shifts, and c-Fos expression in the suprachiasmatic nucleus, while the long-wavelength enriched lighting evoked much weaker responses. Furthermore, exposure of WT mice to the short-wavelength light at night reduced the amplitude of locomotor activity rhythms and impaired social interactions. Mice lacking the melanopsin expressing ipRGCs (Opn4DTA mice) were resistant to these negative effects of DLaN. Importantly, the shift of the DLaN stimulus to longer wavelengths ameliorated the negative impact on the activity rhythms and autistic behaviors (i.e. reciprocal social interactions, repetitive grooming) of the Cntnap2 KO model. The short-, but not the long-wavelength enriched, DLaN triggered cFos expression in the peri-habenula region as well as in the basolateral amygdala (BLA). Finally, DLaN-driven c-Fos induction in BLA glutamatergic neurons was about 3-fold higher in the Cntnap2 KO mice, suggesting that these cells may be particularly vulnerable to the effects of photic disruption. Broadly, our findings suggest that the spectral properties of light at night should be considered in the management of ASD and other neurodevelopmental disorders.

neuroscience↗

bioRxiv2021

In search of a core cellular network in single cell transcriptome data

Along with specialized functions, cells of multicellular organisms also perform essential functions. Whether diverse cells do this by using the same set of genes, interacting in a fixed coordinated fashion, remains a central question in biology. Single-cell RNA-sequencing (scRNA-seq) measures gene expression of individual cells, enabling researchers to discover gene expression patterns that contribute to the diversity of cell functions. Current efforts focus primarily on identifying differentially expressed genes. However, patterns of co-expression between genes are more indicative of biological processes than are the expression of individual genes. Here, we constructed cell type-specific gene co-expression networks using the fly brain transcriptome atlas to search for a core cellular network. We detected a set of highly coordinated genes preserved across cell types and defined this set as the core network. This network was further validated through two additional datasets profiling fly brains or heads. This core has a small size and shows dense connectivity. Modules within this core are enriched for basic cellular functions and gene members of these modules have distinct evolutionary signatures. Overall, we demonstrated that a core cellular network exists in diverse cell types of fly brains and this core exhibits unique topological, structural, functional and evolutionary properties.

genomics↗

bioRxiv2021

Microbiota links to neural dynamics supporting threat processing

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive-interoceptive appraisal of threat-related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling, and computational modelling in healthy participants. Results showed interactions between high-level ecological indices with threat-related AIC-dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota-derived metabolites in the observed relationship with threat-related brain processes.

neuroscience↗

bioRxiv2020

Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

To understand the genetic basis and selective forces acting on longevity, it is useful to examine lifespan variation among closely related species, or ecologically diverse isolates of the same species, within a controlled environment. In particular, this approach may lead to understanding mechanisms underlying natural variation in lifespan. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered a wide diversity of replicative lifespan. Phylogenetic analyses pointed to genes and environmental factors that strongly interact to modulate the observed aging patterns. We then identified genetic networks causally associated with natural variation in replicative lifespan across wild yeast isolates, as well as genes, metabolites and pathways, many of which have never been associated with yeast lifespan in laboratory settings. In addition, a combined analysis of lifespan-associated metabolic and transcriptomic changes revealed unique adaptations to interconnected amino acid biosynthesis, glutamate metabolism and mitochondrial function in long-lived strains. Overall, our multi-omic and lifespan analyses across diverse isolates of the same species shows how gene-environment interactions shape cellular processes involved in phenotypic variation such as lifespan.

genetics↗

bioRxiv2020

Genetic Analysis of Methyl Anthranilate, Mesifurane, Linalool and Other Flavor Compounds in Cultivated Strawberry (Fragaria xananassa)

The cultivated strawberry (Fragaria xananassa) is an economically important fruit crop that is intensively bred for improved sensory qualities. The diversity of fruit flavors and aromas in strawberry result mainly from the interactions of sugars, acids, and volatile organic compounds (VOCs) that are derived from diverse biochemical pathways influenced by the expression of many genes. This study integrates multi-omics analyses to identify QTL and candidate genes for multiple aroma compounds in a complex strawberry breeding population. Novel fruit volatile QTL were discovered for methyl anthranilate, methyl 2-hexenoate, methyl 2-methylbutyrate, mesifurane, and a shared QTL on Chr 3 was found for nine monoterpene and sesquiterpene compounds, including linalool, 3-carene, {beta}-phellandrene, -limonene, linalool oxide, nerolidol, -caryophellene, -farnesene, and {beta}-farnesene. Fruit transcriptomes from a subset of sixty-four individuals were used to support candidate gene identification. For methyl esters including the grape-like methyl anthranilate, a novel ANTHANILIC ACID METHYL TRANSFERASE-like gene was identified. Two mesifurane QTL correspond with the known biosynthesis gene O-METHYL TRANSFERASE 1 and a novel FURANEOL GLUCOSYLTRANSFERASE. The shared terpene QTL contains multiple fruit-expressed terpenoid pathway-related genes including NEROLIDOL SYNTHASE 1 (FanNES1). The abundance of linalool and other monoterpenes is partially governed by a co-segregating expression-QTL (eQTL) for FanNES1 transcript variation, and there is additional evidence for quantitative effects from other terpenoid-pathway genes in this narrow genomic region. These QTL present new opportunities in breeding for improved flavor in commercial strawberry.

plant biology↗

bioRxiv2019

Brain Aging in Major Depressive Disorder: Results from the ENIGMA Major Depressive Disorder working group

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset. MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain predicted age difference (brain-PAD). FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohens d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004). InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates. FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

neuroscience↗

bioRxiv2018

Neuropathy and neural plasticity in the subcutaneous white adipose depot.

The difficulty in obtaining as well as maintaining weight loss, together with the loss of metabolic control in conditions like diabetes and cardiovascular disease, may represent pathological situations of inadequate neural communication between the brain and peripheral organs and tissues. Innervation of adipose tissues by peripheral nerves provides a means of communication between the master metabolic regulator in the brain (chiefly the hypothalamus), and energy-expending and energy-storing cells in the body (primarily adipocytes). Although chemical and surgical denervation studies have clearly demonstrated how crucial adipose tissue neural innervation is for maintaining proper metabolic health, we have uncovered that adipose tissue becomes neuropathic in various conditions of metabolic dysregulation. Here, utilizing both human and mouse adipose tissues, we present evidence of adipose tissue neuropathy, or loss of innervation, under pathophysiological conditions such as obesity, diabetes, and aging, all of which are concomitant with insult to the adipose organ and metabolic dysfunction. Neuropathy is indicated by loss of nerve fiber protein expression, reduction in synaptic markers, and less neurotrophic factor expression in adipose tissue. Aging-related adipose neuropathy particularly results in loss of innervation around the tissue vasculature. These findings underscore that peripheral neuropathy is not restricted to classic tissues like the skin of distal extremities, and that loss of innervation to adipose may trigger or exacerbate metabolic diseases. In addition, we have demonstrated stimulation of adipose tissue neural plasticity with exercise, cold exposure or neurotrophic factor treatment, which may ameliorate adipose neuropathy and be a potential therapeutic option to re-innervate adipose and restore metabolic health.

neuroscience↗

bioRxiv2018

Functional Connectivity of Corticostriatal Circuitry and Psychosis-Like Experiences in the General Community

BackgroundPsychotic symptoms are proposed lie on a continuum, ranging from isolated psychosis-like experiences (PLEs) in non-clinical populations to frank disorder. Here, we investigate neurobiological correlates of this symptomatologic continuum by examining whether functional connectivity of dorsal corticostriatal circuitry, which is disrupted in patients and high-risk individuals, is associated with the severity of subclinical PLEs.\n\nMethodsA community sample of 672 adults with no history of psychiatric or neurological illnesses completed a battery of seven questionnaires spanning various PLE domains. Principal component analysis (PCA) estimated major dimensions of PLEs from the questionnaires. PCA dimension scores were then correlated with whole-brain voxelwise functional connectivity (FC) maps of the striatum in a subset of 353 participants who completed a resting-state neuroimaging protocol.\n\nResultsPCA identified two dimensions of PLEs accounting for 62.57% of variance in the measures, corresponding to positive and negative PLEs. Reduced FC between the dorsal striatum and prefrontal cortex correlated with higher positive PLEs. Negative PLEs correlated with increased FC between the dorsal striatum and visual and sensorimotor areas. In the ventral corticostriatal system, positive and negative PLEs were both associated with FC between the ventro-rostral putamen and sensorimotor cortices.\n\nConclusionsConsistent with past findings in patients and high-risk individuals, subthreshold positive symptomatology is associated with reduced FC of the dorsal circuit. These findings suggest that the connectivity of this circuit tracks the expression of psychotic phenomena across a broad spectrum of severity, extending from the subclinical domain to clinical diagnosis.

neuroscience↗